Articular cartilage degradation is a classical feature of both degenerative and inflammatory arthritides e.g. osteoarthritis (OA) and rheumatoid arthritis (RA). OA is characterised by a loss of the proteoglycans and collagen in the extracellular matrix (ECM), and these catabolic events are primarily mediated by the matrix metalloproteinases (MMPs 1, 3, 9, and 13 (1-6)) and aggrecanases (ADAMTS-4 and -5 (6-8)). The differential expression of these catabolic enzymes is related to the level of inflammatory mediators and cytokines in the OA joint. Cytokines such as interleukin-1 (IL-1) and tumour necrosis factor-α (TNF-α) are key mediators in driving ECM destruction. In addition to inducing the synthesis of MMPs and aggrecanases, IL-1 and TNF-α also stimulate production of nitric oxide, via inducible nitric oxide synthase, and increase the synthesis of prostaglandin E2 (PGE2), by stimulating the expression of PGE2 synthase and cyclo-oxygenase 2 (COX-2).
The incidence of OA is prevalent in an ageing or obese population; there are estimates of 100 million people with OA in the European Union (9), and in the United States, the burden of clinical OA has risen to nearly 27 million people in 2007 (10). Relieving pain and stiffness, improving physical function and delaying disease progression are important therapeutic goals for managing OA. Non-opioid analgesics, non-steroidal anti-inflammatory drugs (NSAIDs) and intra-articular therapies are currently prescribed; continued use of NSAIDs has been associated with G.I. tract bleeding, and an increased risk of other adverse side effects (11), making them far from ideal for treating a chronic pathology. Therefore, identifying other potential pharmaceutical agents which may be used to alleviate the symptoms associated with OA, whilst remaining efficacious and non-toxic, is an ongoing pursuit.
However, as will be apparent to those skilled in the art, the medicament described herein has application in the treatment of any inflammatory condition in which MMP9, PGE2 and NO are elevated or which are Interleukin-1 mediated such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), sepsis, sepsis syndrome, osteoporosis, ischemic injury, graft vs. host disease, reperfusion injury, asthma, diabetes, cancer, myelogenous and other leukemias, psoriasis and cachexia, Alzheimer's Disease, demyelinating neurological disorders including multiple sclerosis, retinal disorders, neurological, retinal, and muscular disorders.
In recent years, there has been a growing interest in the use of compounds derived from herbs in alleviating the symptoms of a variety of diseases such as OA, breast and prostate cancer, neuronal plasticity/memory loss, encephalomyelitis and inflammatory bowel disease.
Preparations from the oleo resin of the Boswellia genus (other than B. frereana), commonly known as frankincense, have been identified as potent anti-inflammatory, anti-arthritic and anti-analgesic agents (recently reviewed in (15, 16)). Traditionally, Boswellia serrata species has been used extensively in treating conditions which are either initiated by or maintained by inflammatory events, including collagenous colitis (17), Crohn's disease (18), and both rheumatoid (19, 20) and osteoarthritis (21-23). The studies demonstrated that B. serrata had some efficacy in treating these inflammatory conditions. In two different animal models of arthritis (carrageenan-induced and antigen-induced), topical administration of B. serrata to the site of inflammation reduced rat paw edema by approximately 50% (20). The main pharmacologically active ingredients of B. serrata are α- and β-boswellic acids (24), and Singh et al intimated that the α- or β-boswellic acid was able to act in both early and late phases of inflammation (20). B. serrata is believed to exert its anti-inflammatory properties by inhibiting 5-lipoxygenase in a selective, enzyme-linked non-redox and non-competitive manner (25), and by inhibiting COX-1 activity (26).
Recently, the efficacy of 5-Loxin®, a novel B. serrata extract enriched with 30% 3-O-acetyl-11-keto-β-boswellic acid, has been tested in human clinical trials for the treatment of knee OA (23). Significant improvements in pain score and functional ability, and a reduction in synovial fluid MMP 3 were observed (23).
Apart from B. serrata (native to India), other members of the Boswellia family have also been identified including B. sacra (native to Arabian peninsula) and B. carteri (27) and frereana (native to Africa).
Our work has shown that B. frereana does not contain boswellic acid (alpha or beta), the main pharmacologically active ingredient of B. Serrata, it is therefore surprising to discover that B. frereana is effective as an anti-inflammatory and interesting to discover that this anti-inflammatory effect operates via a different pathway to that used by other members of the Boswellian genus. Indeed we have discovered that the pharmacologically active component(s) of B. frereana operates, at least partly, via the suppression, deactivation or inhibition of matrix metalloproteinase 9 (MMP9). Additionally, we have also discovered that B. frereana inhibits acetylcholinesterase activity and so this makes it useful for treating neurological disorders where inhibition of acetylcholinesterase is of benefit, such as Alzheimer's disease. Moreover, we have also shown that B. frereana is effective at killing cancer cells and so this makes it useful for treating cancer, in particular breast cancer.